This project examined neuronal and glial cells and interaction/signalling between these cells in nervous system injury. Within the nervous system cytokines are thought to have an active role in the pathophysiology of various neurological diseases and trauma. Early responses to chemical injury suggest a possible involvement of pro-inflammatory cytokines in the signalling process to initiate an injury response cascade of microglia activation, astrogliosis, neuronal necrosis and loss. We have demonstrated a spato-temporal pattern of response for pro-inflammatory cytokines in chemical-induced injury. The induction of mRNA for TNFa and interleukins shows a differential response with regard to type of chemical-induced injury, hippocampal neurons (trimethyltin - TMT) vs. myelin edema(triethyltin) however, with a consistent early response of MIP-1alpha. With hippocampal neurodegeneration mRNA levels for TNFalpha, IL-1alpha, IL-1beta, IL-6, MIP-1alpha, TGF-beta1, ICAM-1, EB-22, and GFAP were elevated within the first few days after TMT injection. In situ hybridization demonstrated the cellular localization of TNFalpha and IL-1alpha in microglia while the protective cytokine TGF-beta 1 was localized in the surviving neurons suggesting a role for TGFbeta in determining the differential sensitivity of neurons to injury. In vivo pharmacological intervention with anti-inflammatory agents or a cocktail of neutralizing anti-bodies to the pro-inflammatory cytokines has not been successful in preventing either the cytokine response or the neuronal degeneration suggesting a more complicated multi-facted process involved in chemical-induced neurodegeneration than that found in vitro. In the op/op mutant mice, lack of functional colony stimulating factor-1 as a mitogen for microglia produced more severe hippocampal neurodegeneration suggesting that the actual number of microglia is not a critical factor in the degenerative process. Future Research: Research will continue to address if the microglia response and associated cytokine or toxic product formation and release are critical for astrocyte reactivity and neurodegeneration. This will be conducted with the use of both pharmacological interventions, (cytokine antibodies, protease inhibitors, free radical scavangers) and specific transgenic mouse models such as the bcl2 overexpressor, COX1 & COX2 knockout,each involved in the process of neuronal apoptosis and astrocyte second messenger system, respectively.